In 2012, I had the distinct honor of being part of one of the trailblazing teams leading first-in-human/first-in-child chimeric antigen receptor (CAR) T cell trials in B cell acute lymphoblastic leukemia (B-ALL). Little did I know then that we were only at the tip of the iceberg for use of immunotherapy in pediatric oncology. While the multiple CAR T cell approvals for B cell malignancies, including in pediatric B-ALL, reflect the curative potential in relapsed/refractory disease, what has additionally transpired is a cascade of novel immune-effector cell therapy-based approaches, each iteratively building upon the prior to further extend the therapeutic index of immunotherapy.